chr19-40394272-TTCCTCC-T

Variant names:

• chr19-40394272-TTCCTCC-T
• rs139624657
• NM_181882.3:c.4074_4079delGGAGGA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_181882.3(PRX):​c.4074_4079delGGAGGA​(p.Glu1359_Glu1360del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,604,056 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: PRX NM_181882.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.16

Genes affected

PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-40394272-TTCCTCC-T is Benign according to our data. Variant chr19-40394272-TTCCTCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 242184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40394272-TTCCTCC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00435 (658/151328) while in subpopulation AFR AF= 0.0149 (615/41338). AF 95% confidence interval is 0.0139. There are 3 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3	c.4074_4079delGGAGGA	p.Glu1359_Glu1360del	disruptive_inframe_deletion	Exon 7 of 7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.4359_4364delGGAGGA	p.Glu1454_Glu1455del	disruptive_inframe_deletion	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2	c.3972_3977delGGAGGA	p.Glu1325_Glu1326del	disruptive_inframe_deletion	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2	c.*4279_*4284delGGAGGA		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.4074_4079delGGAGGA	p.Glu1359_Glu1360del	disruptive_inframe_deletion	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 657 AN: 151212 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00289

GnomAD3 exomes AF: 0.00169 AC: 246 AN: 145830 Hom.: 1 AF XY: 0.00127 AC XY: 99 AN XY: 78150

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000695

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000321

GnomAD4 exome AF: 0.000481 AC: 699 AN: 1452728 Hom.: 6 AF XY: 0.000359 AC XY: 259 AN XY: 722292

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.000567

GnomAD4 genome AF: 0.00435 AC: 658 AN: 151328 Hom.: 3 Cov.: 32 AF XY: 0.00448 AC XY: 331 AN XY: 73926

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000591

Gnomad4 OTH AF: 0.00286

Bravo AF: 0.00501

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 10, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139624657; hg19: chr19-40900179;